Excess thyroid hormone is a significant cause of secondary osteoporosis. Although it is well established that thyroid hormones have a direct effect, on bone to increase resorption, the mechanism of the effect has not been fully elucidated. Thyroid hormones do not produce complete resorption in vitro. Also, their effects are biphasic. Interactions of thyroid hormones with the immune system and the effects of immunosuppressive agents to inhibit thyroid hormone-stimulated bone resorption suggest that cytokines might mediate or modulate thyroid hormone action on bone. To investigate, this further, we will determine the effects of thyroid hormones on the secretion of certain cytokines in cultures of fetal rat limb bones and UMR- 106 osteoblastic osteosarcoma cells. IL-1alpha and beta, IL-6, TNFalpha, TGFbeta and IGF-I local factors that affect bone metabolism will be measured in cultures incubated with thyroxine, triiodothyronine and with the inactive analogs, reverse triiodothyronine or diiodotyrosine. Effects of available neutralizing antibodies and the interleukin receptor antagonist protein on the action of thyroid hormones to stimulate resorption (in the cultures) and osteocalcin production (in the cells) will be determined. Since thyroid hormones stimulate prostaglandin production in some tissues, cyclooxygenase inhibitors will be used to assess the relationship of prostaglandin production to the secretion of the local factors. Studies on thyroid hormone effects on mRNA for cytokines identified as possible mediators will be initiated.